TY - JOUR
T1 - Cancer-derived exosomes trigger endothelial to mesenchymal transition followed by the induction of cancer-associated fibroblasts
AU - Yeon, Ju Hun
AU - Jeong, Hyo Eun
AU - Seo, Hyemin
AU - Cho, Siwoo
AU - Kim, Kimin
AU - Na, Dokyun
AU - Chung, Seok
AU - Park, Jaesung
AU - Choi, Nakwon
AU - Kang, Ji Yoon
N1 - Funding Information:
This work was supported by Technology Innovation Program (10067787) of Korea Evaluation Institute of Industrial Technology (KEIT) funded by Ministry of Trade, Industry, and Energy. This research was also supported by National Research Foundation of Korea (NRF) funded by Ministry of Science and ICT (NRF-2017M3A7B4049851 and NRF-2016R1C1B2013345). This work was also supported by the Institutional Program (Project Nos. 2E28411 and 2E27910) of Korea Institute of Science and Technology (KIST).
Funding Information:
This work was supported by Technology Innovation Program (10067787) of Korea Evaluation Institute of Industrial Technology (KEIT) funded by Ministry of Trade, Industry, and Energy. This research was also supported by National Research Foundation of Korea (NRF) funded by Ministry of Science and ICT (NRF- 2017M3A7B4049851 and NRF- 2016R1C1B2013345 ). This work was also supported by the Institutional Program (Project Nos. 2E28411 and 2E27910) of Korea Institute of Science and Technology (KIST).
Publisher Copyright:
© 2018 Acta Materialia Inc.
PY - 2018/8
Y1 - 2018/8
N2 - Cancer-associated fibroblasts (CAFs) play a pivotal role in tumor growth, but very little has been known about its characteristics and origin. Recently, cancer-derived exosome has been suggested to transdifferentiate CAFs, by a new mechanism of endothelial to mesenchymal transition (EndMT), initiating angiogenic processes and triggering metastatic evolution. However, an enabling tool in vitro is yet to be developed to investigate complicated procedures of the EndMT and the transdifferentiation under reconstituted tumor microenvironment. Here we proposed an in vitro microfluidic model which enables to monitor a synergetic effect of complex tumor microenvironment in situ, including extracellular matrix (ECM), interstitial flow and environmental exosomes. The number of CAFs differentiated from human umbilical vein endothelial cells (HUVECs) increased with melanoma-derived exosomes, presenting apparent morphological and molecular changes with pronounced motility. Mesenchymal stem cell (MSC)-derived exosomes were found to suppress EndMT, induce angiogenesis and maintain vascular homeostasis, while cancer-derived exosomes promoted EndMT. Capabilities of the new microfluidic model exist in precise regulation of the complex tumor microenvironment and therefore successful reconstitution of 3D microvasculature niches, enabling in situ investigation of EndMT procedure between various cell types. Statement of Significance: This study presents an in vitro 3D EndMT model to understand the progress of the CAF generation by recapitulating the 3D tumor microenvironment in a microfluidic device. Both cancer-derived exosomes and interstitial fluid flow synergetically played a pivotal role in the EndMT and consequent formation of CAFs through a collagen-based ECM. Our approach also enabled the demonstration of a homeostatic capability of MSC-derived exosomes, ultimately leading to the recovery of CAFs back to endothelial cells. The in vitro 3D EndMT model can serve as a powerful tool to validate exosomal components that could be further developed to anti-cancer drugs.
AB - Cancer-associated fibroblasts (CAFs) play a pivotal role in tumor growth, but very little has been known about its characteristics and origin. Recently, cancer-derived exosome has been suggested to transdifferentiate CAFs, by a new mechanism of endothelial to mesenchymal transition (EndMT), initiating angiogenic processes and triggering metastatic evolution. However, an enabling tool in vitro is yet to be developed to investigate complicated procedures of the EndMT and the transdifferentiation under reconstituted tumor microenvironment. Here we proposed an in vitro microfluidic model which enables to monitor a synergetic effect of complex tumor microenvironment in situ, including extracellular matrix (ECM), interstitial flow and environmental exosomes. The number of CAFs differentiated from human umbilical vein endothelial cells (HUVECs) increased with melanoma-derived exosomes, presenting apparent morphological and molecular changes with pronounced motility. Mesenchymal stem cell (MSC)-derived exosomes were found to suppress EndMT, induce angiogenesis and maintain vascular homeostasis, while cancer-derived exosomes promoted EndMT. Capabilities of the new microfluidic model exist in precise regulation of the complex tumor microenvironment and therefore successful reconstitution of 3D microvasculature niches, enabling in situ investigation of EndMT procedure between various cell types. Statement of Significance: This study presents an in vitro 3D EndMT model to understand the progress of the CAF generation by recapitulating the 3D tumor microenvironment in a microfluidic device. Both cancer-derived exosomes and interstitial fluid flow synergetically played a pivotal role in the EndMT and consequent formation of CAFs through a collagen-based ECM. Our approach also enabled the demonstration of a homeostatic capability of MSC-derived exosomes, ultimately leading to the recovery of CAFs back to endothelial cells. The in vitro 3D EndMT model can serve as a powerful tool to validate exosomal components that could be further developed to anti-cancer drugs.
KW - Cancer-associated fibroblasts
KW - Cancer-derived exosomes
KW - Endothelial to mesenchymal transition
KW - Interstitial flow
KW - Microfluidic culture
UR - http://www.scopus.com/inward/record.url?scp=85049579473&partnerID=8YFLogxK
U2 - 10.1016/j.actbio.2018.07.001
DO - 10.1016/j.actbio.2018.07.001
M3 - Article
C2 - 30078422
AN - SCOPUS:85049579473
SN - 1742-7061
VL - 76
SP - 146
EP - 153
JO - Acta Biomaterialia
JF - Acta Biomaterialia
ER -
